Induction of Cyclooxygenase-2 by Angiotensin II in Cultured Rat Vascular Smooth Muscle Cells

Abstract

Abstract-Angiotensin II (Ang II) stimulates the release of prostaglandins (PGs) in various cells and tissues. Recently, cyclooxygenase-2 (COX-2) emerged as a new key regulator for PG synthesis. In the present study, we investigated whether Ang II regulates COX-2 expression in cultured rat vascular smooth muscle cells (VSMCs). Ang II markedly increased the expression of COX-2 mRNA in a time-and dose-dependent manner. This effect was completely blocked by the Ang II type 1 receptor antagonist losartan but not by the Ang II type 2 receptor antagonist PD123319. The p42/44 mitogen-activated protein kinase (MAPK) kinase-1 inhibitor PD98059 and the p38 MAPK inhibitor SB203580 significantly suppressed Ang II-induced COX-2 mRNA and protein expression. Ang II did not increase transcription of the COX-2 gene, as examined with a COX-2 promoter/luciferase chimeric plasmid construct. Instead, it suppressed the degradation of COX-2 mRNA. PD98059 and SB203580 markedly enhanced the decay of COX-2 mRNA induced by Ang II, implying that p42/44 and p38 MAPK activated by Ang II play a role in the regulation of COX-2 through stabilization of its mRNA. The COX-2-specific inhibitor NS-398 attenuated Ang II-stimulated DNA and protein synthesis, as well as PGE 2 production by VSMCs. These results suggest that Ang II regulates COX-2 expression and PG production and modulates cell proliferation through MAPK-mediated signaling pathways in rat VSMCs.

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…37,54 Our results demonstrating that an increase in COX-2 expression in Ang IIeinduced AAA in Apoe À/À /Cyp1b1 þ/þ mice was prevented by TMS or Cyp1b1 gene disruption suggests that CYP1B1 acts upstream of COX-2 in minimizing AAA, which could be due to ROSs generated by CYP1B1. Supporting this view was our finding that the administration of tempol attenuated the expression of COX-2, which could occur via p38 MAPK, as reported in previous studies.…”

“…35 The infusion of Ang II for 28 days increased aortic ROSs, as indicated by enhanced oxidized DHE fluorescence intensity in AAA ( Figure 5, A and B), and cardiac NADPH oxidase activity and increased plasma levels of 8-isoprostane, another index of oxidative stress, 36 in Apoe À/À /Cyp1b1 þ/þ mice, which was inhibited by treatment with TMS or by Cyp1b1 gene disruption ( Figure 5, C and D). Ang II increases COX-2 expression in VSMCs via p38 mitogen-activated protein kinase, 37 and this pathway been implicated in the pathogenesis of AAA. 38 Therefore, we determined the contribution of CYP1B1 to the expression of COX-2 in Ang IIeinduced AAA.…”

Growth Factors and COX2 Expression in Canine Perivascular Wall Tumors

“…44 A further role of the TGFb superfamily is to regulate COX2 secretion in hypoxic tissues; hypoxia itself represents an additional trigger for MCs proliferation. 35,45 Simultaneous high expression of TGFb1 and the 2 corresponding receptors was evident in 4 of 40 PWTs. Based on these findings, the TGFb1 pathway seems to play a minor role in canine PWTs pathogenesis.…”

“…Interestingly, in this study, TGFb1 expression was significantly associated with COX2 expression, supporting the presence of a link between these 2 molecules, as demonstrated by previous studies. 35,45 COX2 was detected in a minority of tumors. This result was expected since COX2 expression has been reported mainly in epithelial tumors, 14,20 while its presence in mesenchymal neoplasm is inconstant and rarely has a prognostic relevance.…”

Role of Prostaglandin E Receptor EP 1 Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

“…28,29 There is no doubt that the renin-angiotensin system is activated and angiotensin II plays a critical role in the progression of renal injury in SHRSP. 30,31 The present study showed marked upregulation of cyclooxygenase-2 expression in cultured mesangial cells from SHRSP.…”